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PURPOSE: We describe the fibrotic rim formed in the desmoplastic growth pattern (DHGP) of colorectal cancer liver metastasis (CLM) using in situ sequencing (ISS). The origin of the desmoplastic rim is still a matter of debate, and the detailed cellular organization has not yet been fully elucidated. Understanding the biology of the DHGP in CLM can explore targeted treatment to improve survival. EXPERIMENTAL DESIGN: We used ISS, targeting 150 genes, to characterize the desmoplastic rim by unsupervised clustering of gene co-expression patterns. The cohort comprised 10 chemo-naïve liver metastasis resection samples with a DHGP. RESULTS: Unsupervised clustering of spatially mapped genes revealed molecular and cellular diversity within the desmoplastic rim. We confirmed the presence of the ductular reaction and cancer-associated fibroblasts. Importantly, we discovered angiogenesis and outer and inner zonation in the rim, characterized by NGFR and POSTN expression. CONCLUSIONS: ISS enabled the analysis of the cellular organization of the fibrous rim surrounding CLM with a DHGP and suggests a transition from the outer part of the rim, with nonspecific liver injury response, into the inner part, with gene expression indicating collagen synthesis and extracellular matrix remodeling influenced by the interaction with cancer cells, creating a cancer cell supportive environment. Moreover, we found angiogenic processes in the rim. Our results provide a potential explanation of the origin of the rim in DHGP and lead to exploring novel targeted treatments for patients with CLM to improve survival.
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BACKGROUND: Opting for or against the administration of adjuvant chemotherapy in therapeutic management of stage II colon cancer remains challenging. Several studies report few survival benefits for patients treated with adjuvant therapy and additionally revealing potential side effects of overtreatment, including unnecessary exposure to chemotherapy-induced toxicities and reduced quality of life. Predictive biomarkers are urgently needed. We, therefore, hypothesise that the spatial tissue composition of relapsed and non-relapsed colon cancer stage II patients reveals relevant biomarkers. METHODS: The spatial tissue composition of stage II colon cancer patients was examined by a novel spatial transcriptomics technology with sub-cellular resolution, namely in situ sequencing. A panel of 176 genes investigating specific cancer-associated processes such as apoptosis, proliferation, angiogenesis, stemness, oxidative stress, hypoxia, invasion and components of the tumour microenvironment was designed to examine differentially expressed genes in tissue of relapsed versus non-relapsed patients. Therefore, FFPE slides of 10 colon cancer stage II patients either classified as relapsed (5 patients) or non-relapsed (5 patients) were in situ sequenced and computationally analysed. RESULTS: We identified a tumour gene signature that enables the subclassification of tissue into neoplastic and non-neoplastic compartments based on spatial expression patterns obtained through in situ sequencing. We developed a computational tool called Genes-To-Count (GTC), which automates the quantification of in situ signals, accurately mapping their position onto the spatial tissue map and automatically identifies neoplastic and non-neoplastic tissue compartments. The GTC tool was used to quantify gene expression of biological processes upregulated within the neoplastic tissue in comparison to non-neoplastic tissue and within relapsed versus non-relapsed stage II colon patients. Three differentially expressed genes (FGFR2, MMP11 and OTOP2) in the neoplastic tissue compartments of relapsed patients in comparison to non-relapsed patients were identified predicting recurrence in stage II colon cancer. CONCLUSIONS: In depth spatial in situ sequencing showed potential to provide a deeper understanding of the underlying mechanisms involved in the recurrence of disease and revealed novel potential predictive biomarkers for disease relapse in colon cancer stage II patients. Our open-access GTC-tool allowed us to accurately capture the tumour compartment and quantify spatial gene expression in colon cancer tissue.
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Neoplasias del Colon , Calidad de Vida , Humanos , Pronóstico , Recurrencia Local de Neoplasia/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Biomarcadores de Tumor/genética , Estadificación de Neoplasias , Microambiente Tumoral/genéticaRESUMEN
OBJECTIVES: We aimed to map the correlation between thermoluminescent dosimeters (TLDs) and Gafchromic film for measuring absorbed doses and to compare minimum, maximum, and mean absorbed doses over larger regions of interest and at various craniofacial organs and tissues during cone beam computed tomography (CBCT) exposure of the mandibular third molar region. STUDY DESIGN: We positioned TLDs at 75 measurement points in a head phantom. Gafchromic film was cut to the same shape as the 5 levels of the phantom and was placed on top of the TLDs. Both dosimetry methods thus included the surface of each level simultaneously. CBCT scans were made using a 5 × 5 cm field of view and a rotation angle of 200°. Measurements included absorbed dose distributions, doses at all 75 points, and minimum, maximum, and mean doses within organs and tissues. RESULTS: The correlation of point-dose measurements at all TLD sites with doses measured on film was strong (R2 = 0.9687), with greatest correlation at lower doses (<2 mGy). Large deviations between TLD and film measurements of minimum and maximum doses and absorbed doses to the organs occurred at all 5 levels. TLD positioning failed to cover several organ sites; for these, only absorbed dose measurements from the film were available. CONCLUSIONS: TLDs were unable to sample dose distributions and gradients accurately. The characteristics of Gafchromic LD-V1 film make it a favorable alternative in dental CBCT dosimetry.
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Dosímetros de Radiación , Dosimetría Termoluminiscente , Humanos , Dosis de Radiación , Dosimetría Termoluminiscente/métodos , Tomografía Computarizada de Haz Cónico/métodos , Mandíbula/diagnóstico por imagen , Fantasmas de ImagenRESUMEN
BACKGROUND/AIM: The role of single nucleotide polymorphisms (SNPs) in the frequency and intensity of chemotherapy-induced nausea and vomiting (CINV) in women with breast cancer (BC) is unclear. The primary purpose of this study was to compare/evaluate the effect of SNP-guided antiemetic treatment versus standard CINV treatment. PATIENTS AND METHODS: A randomised, factorial, phase II multicentre study design was used. Women planned for neoadjuvant or adjuvant chemotherapy with epirubicin, cyclophosphamide and fluorouracil (FEC /EC, with or without fluorouracil) for BC were randomised to SNP-guided antiemetic treatment (based on the results of SNP analyses) versus standard CINV treatment. Blood samples were taken before the treatment was initiated. Patient-reported data on CINV (during 10 days from onset of cancer treatment) and health-related quality of life (HRQoL), were collected before and after the first cancer treatment. RESULTS: A total of 188 women were included. Overall, nausea was reported by 86% (n=129) of the patients during the ten-day period from the start of cancer treatment. The SNP genotype studied varied. In FAS-CD95, the genotypes AG and GG were overrepresented; in RB1-LPAR6, GG was overrepresented, and in CCL2, both AA and GG were overrepresented. We found no statistically significant difference in CINV between SNP-guided antiemetic treatment versus standard CINV treatment. CONCLUSION: SNP-guided antiemetic treatment could be as effective as standard treatment. SNP-guided antiemetic treatment of CINV is possibly useful in detecting patients with a higher or lower risk for CINV and thus may help in avoiding over-treatment with toxic components. CINV negatively affects the HRQL.
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Antieméticos , Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/inducido químicamente , Polimorfismo de Nucleótido Simple , Calidad de Vida , Náusea/inducido químicamente , Náusea/tratamiento farmacológico , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológico , Fluorouracilo/efectos adversos , Antineoplásicos/uso terapéutico , Receptores del Ácido LisofosfatídicoRESUMEN
The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of single-cell and spatial multi-omics data, we used 16 prenatal human samples to create a comprehensive developmental cell atlas of the spinal cord during post-conceptional weeks 5-12. This revealed how the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. We identified unique events in human spinal cord development relative to rodents, including earlier quiescence of active neural stem cells, differential regulation of cell differentiation and distinct spatiotemporal genetic regulation of cell fate choices. In addition, by integrating our atlas with pediatric ependymomas data, we identified specific molecular signatures and lineage-specific genes of cancer stem cells during progression. Thus, we delineate spatiotemporal genetic regulation of human spinal cord development and leverage these data to gain disease insight.
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Ependimoma , Células-Madre Neurales , Niño , Femenino , Embarazo , Humanos , Médula Espinal , Ependimoma/genética , Ependimoma/metabolismo , Diferenciación Celular/genética , Células-Madre Neurales/fisiología , Expresión Génica , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica/genéticaRESUMEN
Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
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Glioma , Humanos , Niño , Glioma/genética , Histonas/genética , Metionina , Mutación , Racemetionina , Microambiente Tumoral/genéticaRESUMEN
Genome sequencing of cancers often reveals mosaics of different subclones present in the same tumour1-3. Although these are believed to arise according to the principles of somatic evolution, the exact spatial growth patterns and underlying mechanisms remain elusive4,5. Here, to address this need, we developed a workflow that generates detailed quantitative maps of genetic subclone composition across whole-tumour sections. These provide the basis for studying clonal growth patterns, and the histological characteristics, microanatomy and microenvironmental composition of each clone. The approach rests on whole-genome sequencing, followed by highly multiplexed base-specific in situ sequencing, single-cell resolved transcriptomics and dedicated algorithms to link these layers. Applying the base-specific in situ sequencing workflow to eight tissue sections from two multifocal primary breast cancers revealed intricate subclonal growth patterns that were validated by microdissection. In a case of ductal carcinoma in situ, polyclonal neoplastic expansions occurred at the macroscopic scale but segregated within microanatomical structures. Across the stages of ductal carcinoma in situ, invasive cancer and lymph node metastasis, subclone territories are shown to exhibit distinct transcriptional and histological features and cellular microenvironments. These results provide examples of the benefits afforded by spatial genomics for deciphering the mechanisms underlying cancer evolution and microenvironmental ecology.
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Neoplasias de la Mama , Carcinoma Intraductal no Infiltrante , Evolución Clonal , Células Clonales , Genómica , Femenino , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Evolución Clonal/genética , Células Clonales/metabolismo , Células Clonales/patología , Mutación , Microambiente Tumoral/genética , Secuenciación Completa del Genoma , Transcriptoma , Reproducibilidad de los Resultados , Microdisección , AlgoritmosRESUMEN
Background: Head and neck squamous cell carcinoma (HNSCC) is a disease involving genetic and lifestyle risk factors such as smoking or high-risk papillomavirus (HR-HPV) infections.Objective: This study analyzed 92 single nucleotide polymorphisms (SNPs) associated with smoking and HPV on HNSCC cancer risk and survival among HNSCC patients.Material and methods: Eighty-six HNSCC patients (48 non-smoking and 38 smoking) were consecutively included.Results: Differences were detected in the analysis of survival and SNP genotypes located in the CXCR2 and COMT. Five SNPs in genes PRKDC, TGFb, XRCC1, Cyp2A6 and CTLA4 were found to be different when comparing SNP genotypes in all patients and all controls as a risk of HNSCC. When comparing SNP genotypes among smoking patients and smoking controls, six SNPs in the genes PFR1, IL10, CCL4, IL6, Ku70, and PRF1 were detected. When comparing SNP genotypes, nine SNPs in CHRNA3, PRKDC, CHARNA5, IFN-γ, ESR1, XRCC1, Cyp2A6, CTLA4, and COMT were different in non-smoking patients and non-smoking controls. No association was found between SNP distribution or patient survival and the impact of HR-HPV.Conclusions: The SNPs differed between smokers and non-smokers and could indicate a possible interaction between genetics and smoking. This could play an important role in a better understanding of the pathogenesis of HNSCC.
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Carcinoma de Células Escamosas , Fumar Cigarrillos , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Polimorfismo de Nucleótido Simple , Neoplasias de Cabeza y Cuello/genética , Antígeno CTLA-4/genética , Infecciones por Papillomavirus/complicaciones , Carcinoma de Células Escamosas/genética , Interleucina-10/genética , Interleucina-6/genética , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos X/genéticaRESUMEN
Mycobacterium tuberculosis (Mtb) bacilli are the causative agent of tuberculosis (TB), a major killer of mankind. Although it is widely accepted that local interactions between Mtb and the immune system in the tuberculous granuloma determine whether the outcome of infection is controlled or disseminated, these have been poorly studied due to methodological constraints. We have recently used a spatial transcriptomic technique, in situ sequencing (ISS), to define the spatial distribution of immune transcripts in TB mouse lungs. To further contribute to the understanding of the immune microenvironments of Mtb and their local diversity, we here present two complementary automated bacteria-guided analysis pipelines. These position 33 ISS-identified immune transcripts in relation to single bacteria and bacteria clusters. The analysis was applied on new ISS data from lung sections of Mtb-infected C57BL/6 and C3HeB/FeJ mice. In lungs from C57BL/6 mice early and late post infection, transcripts that define inflammatory macrophages were enriched at subcellular distances to bacteria, indicating the activation of infected macrophages. In contrast, expression patterns associated to antigen presentation were enriched in non-infected cells at 12 weeks post infection. T-cell transcripts were evenly distributed in the tissue. In Mtb-infected C3HeB/FeJ mice, transcripts characterizing activated macrophages localized in apposition to small bacteria clusters, but not in organized granulomas. Despite differences in the susceptibility to Mtb, the transcript patterns found around small bacteria clusters of C3HeB/FeJ and C57BL/6 mice were similar. Altogether, the presented tools allow us to characterize in depth the immune cell populations and their activation that interact with Mtb in the infected lung.
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Mycobacterium tuberculosis , Tuberculosis Ganglionar , Animales , Granuloma/metabolismo , Pulmón , Macrófagos , Ratones , Ratones Endogámicos C57BLRESUMEN
For the women breast cancer (BC) patients included in this retrospective study, the first line of systemic treatment in adjuvant modality for breast cancer (BC) after surgery was fluorouracil, epirubicin and cyclophosphamide (FEC). The aim of our investigation was to analyze the prognostic biomarkers for relapse and death of patients eight to ten years after chemotherapy in association with nausea and vomiting. METHOD: This retrospective study included 114 patients treated between 2010 and 2013. Blood samples for Single Nucleotide Polymorphism (SNP) analysis before the chemotherapy treatment were collected. The medical records were used to determine relapses and death. RESULTS: Sixteen percent relapsed and 9 % died during the follow-up period. SNPs located in the genes ESR and CASP9 were associated with both relapse and death. CONCLUSIONS: Relapse and death were at a relative moderate level and consistent with other studies. Two SNPs in the Estrogen hormone receptor gene ESR1 and the apoptosis execution gene Caspases 9 (Casp9) were found to be associated with a higher risk of relapse and death. These findings suggest the possible value of blood biomarkers in the selection of individual treatments in the clinical setting.
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Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/métodos , Polimorfismo de Nucleótido Simple/genética , Cuidados Posteriores , Neoplasias de la Mama/mortalidad , Femenino , Humanos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The purpose of this study is to investigate exosome-like vesicle (ELV) plasma concentrations and markers of multivesicular body (MVB) biogenesis in skeletal muscle in response to acute exercise. Seventeen healthy [body mass index (BMI): 23.5 ± 0.5 kg·m-2] and 15 prediabetic (BMI: 27.3 ± 1.2 kg·m-2) men were randomly assigned to two groups performing an acute cycling bout in normoxia or hypoxia ([Formula: see text] 14.0%). Venous blood samples were taken before (T0), during (T30), and after (T60) exercise, and biopsies from m. vastus lateralis were collected before and after exercise. Plasma ELVs were isolated by size exclusion chromatography, counted by nanoparticle tracking analysis (NTA), and characterized according to international standards, followed by expression analyses of canonical ELV markers in skeletal muscle. In the healthy normoxic group, the total number of particles in the plasma increased during exercise from T0 to T30 (+313%) followed by a decrease from T30 to T60 (-53%). In the same group, an increase in TSG101, CD81, and HSP60 protein expression was measured after exercise in plasma ELVs; however, in the prediabetic group, the total number of particles in the plasma was not affected by exercise. The mRNA content of TSG101, ALIX, and CD9 was upregulated in skeletal muscle after exercise in normoxia, whereas CD9 and CD81 were downregulated in hypoxia. ELV plasma abundance increased in response to acute aerobic exercise in healthy subjects in normoxia, but not in prediabetic subjects, nor in hypoxia. Skeletal muscle analyses suggested that this tissue did not likely play a major role of the exercise-induced increase in circulating ELVs.
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Ejercicio Físico , Vesículas Extracelulares/metabolismo , Hipoxia/sangre , Cuerpos Multivesiculares/metabolismo , Contracción Muscular , Estado Prediabético/sangre , Músculo Cuádriceps/metabolismo , Adulto , Ciclismo , Proteínas de Unión al Calcio/sangre , Estudios de Casos y Controles , Proteínas de Ciclo Celular/sangre , Proteínas de Unión al ADN/sangre , Complejos de Clasificación Endosomal Requeridos para el Transporte/sangre , Humanos , Hipoxia/diagnóstico , Hipoxia/fisiopatología , Masculino , Persona de Mediana Edad , Biogénesis de Organelos , Estado Prediabético/diagnóstico , Estado Prediabético/fisiopatología , Músculo Cuádriceps/fisiopatología , Distribución Aleatoria , Tetraspanina 29/sangre , Factores de Tiempo , Factores de Transcripción/sangreRESUMEN
In-vitro incubation of environmental samples is a common approach to estimate CH4 oxidation potential. Here we developed and verified an in-situ method utilizing passive diffusion chambers (PDC, silicone tubes) to deliver 13C-labeled CH4 into peat for the determination of the CH4 oxidation potential based on 13C excess of CO2. To target CH4 oxidation under semi-aerobic and anaerobic conditions, we installed 20 PDCs (30 ml volume) below the water table in profiles from 35-cm to 2-m depths of a peatland in north-eastern Sweden in July 2017 using a peat auger. 13C-labeled CH4 was injected into PDCs through tubing twice during 12 days (day 0 and 6) and samples were collected at days 1, 3, 6, 8 and 11. Background (non-labeled) δ13C of CO2 ranged from -7.3 (35 cm) to +5.7 (200 cm) with depth. These δ13C values rose to +110 and + 204 after the CH4 injection. The estimated CH4-derived C in CO2 was the lowest at the bottom of the profile (0.3 µmol L-1), whereas the maximum was at 100 cm (6.1 µmol L-1) at five days after the second labeling. This corresponded to 1.5-7.2% of the total CH4 pool to be oxidized, depending on depth. This novel approach with belowground in-situ 13C labeling of gases demonstrated the suitability of tracing the transformations of these gases in soil depth by PDCs and for the first time verified the in-situ occurrence of a deep-peat CH4 oxidation.
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Metano , Suelo , Dióxido de Carbono/análisis , Gases , Oxidación-ReducciónRESUMEN
We investigated the effects of a novel multi-ingredient supplement comprised of polyphenol antioxidants and compounds known to facilitate mitochondrial function and metabolic enhancement (ME) in a mouse model of obesity. In this study, 6-week-old male C57/BL6J mice were placed on a high-fat diet (HFD; ~60% fat) for 6 weeks, with subsequent allocation into experimentalgroups for 4 weeks: HFD control, HFD + ME10 (10 components), HFD + ME7 (7 components), HFD + ME10 + EX, HFD + EX (where '+EX' animals exercised 3 days/week), and chow-fed control. After the intervention, HFD control animals had significantly greater body weight and fat mass. Despite the continuation of HFD, animals supplemented with multi-ingredient ME or who performed exercise training showed an attenuation of fat mass and preservation of lean body mass, which was further enhanced when combined (ME+EX). ME supplementation stimulated the upregulation of white and brown adipose tissue mRNA transcripts associated with mitochondrial biogenesis, browning, fatty acid transport, and fat metabolism. In WAT depots, this was mirrored by mitochodrial oxidative phosphorylation (OXPHOS) protein expression, and increased in vivo fat oxidation measured via CLAMS. ME supplementation also decreased systemic and local inflammation markers. Herein, we demonstrated that novel multi-ingredient nutritional supplements induced significant fat loss independent of physical activity while preserving muscle mass in obese mice. Mechanistically, these MEs appear to act by inducing a browning program in white adipose tissue and decreasing other pathophysiological impairments associated with obesity, including mitochondrial respiration alterations induced by HFD.
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Tejido Adiposo Pardo/fisiología , Tejido Adiposo Blanco/fisiología , Dieta Alta en Grasa , Suplementos Dietéticos , Conducta Alimentaria , Aumento de Peso/fisiología , Animales , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Circulación Sanguínea , Respiración de la Célula , Epidídimo/metabolismo , Metabolismo de los Lípidos/genética , Masculino , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Biogénesis de Organelos , Oxidación-Reducción , Fosforilación Oxidativa , Fosforilación , Condicionamiento Físico Animal , ARN Mensajero/genética , ARN Mensajero/metabolismo , Superóxido Dismutasa/metabolismo , Regulación hacia Arriba , Pérdida de PesoRESUMEN
The Human Developmental Cell Atlas (HDCA) initiative, which is part of the Human Cell Atlas, aims to create a comprehensive reference map of cells during development. This will be critical to understanding normal organogenesis, the effect of mutations, environmental factors and infectious agents on human development, congenital and childhood disorders, and the cellular basis of ageing, cancer and regenerative medicine. Here we outline the HDCA initiative and the challenges of mapping and modelling human development using state-of-the-art technologies to create a reference atlas across gestation. Similar to the Human Genome Project, the HDCA will integrate the output from a growing community of scientists who are mapping human development into a unified atlas. We describe the early milestones that have been achieved and the use of human stem-cell-derived cultures, organoids and animal models to inform the HDCA, especially for prenatal tissues that are hard to acquire. Finally, we provide a roadmap towards a complete atlas of human development.
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Movimiento Celular , Rastreo Celular , Células/citología , Biología Evolutiva/métodos , Embrión de Mamíferos/citología , Feto/citología , Difusión de la Información , Organogénesis , Adulto , Animales , Atlas como Asunto , Técnicas de Cultivo de Célula , Supervivencia Celular , Visualización de Datos , Femenino , Humanos , Imagenología Tridimensional , Masculino , Modelos Animales , Organogénesis/genética , Organoides/citología , Células Madre/citologíaRESUMEN
INTRODUCTION: It has been suggested that age could influence the treatment-induced side effects and survival time of cancer patients. The influence of age on blood-based biomarkers, acute radiation skin reactions (ARSRs), and survival time of breast cancer patients was analysed. MATERIALS AND METHODS: Two hundred ninety-three individuals, 119 breast cancer patients, and 174 healthy blood donors were included. RESULTS: Before radiotherapy (RT), decreased levels of lymphocytes, interleukin 2, platelet-derived growth factors, and tumour necrosis factor but increased levels of monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio, C-reactive protein, and macrophage inflammatory protein 1b (MIP1b) were detected in the patient group. All of the patients developed ARSRs and intensity of ARSRs was inversely related to the MIP1b level before RT. Fifteen out of 119 (13%) patients deceased during follow-up time. No influence of age (≤50 compared to >50 years) on survival time was detected (p = 0.442). Tumour recurrence, found in 11 out of 119 (9%) patients, had impact on survival time of these patients (p < 0.001). CONCLUSIONS: The level of circulating MIP1b before RT was associated with intensity of ARSRs. Tumour recurrence, but not age, was associated with poor survival time. Analysis of circulating MIP1b was low cost, rapid, and could be done in routine laboratory facility. Since RT almost always induces ARSRs, the possibility of using MIP1b as a prognostic biomarker for ARSRs is of interests for further investigation.
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Proteínas Adaptadoras Transductoras de Señales/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Radiodermatitis/sangre , Radiodermatitis/etiología , Radioterapia Adyuvante/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Neoplasias de la Mama/radioterapia , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Recuento de Linfocitos , Linfocitos/metabolismo , Persona de Mediana Edad , Monocitos , Neutrófilos/metabolismo , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: Cigarette smoke is suggested to be a risk factor for coronary artery disease (CAD), urinary bladder cancer (UBCa) or lung cancer (LCa). However, not all heavy smokers develop these diseases and elevated cancer risk among first-degree relatives suggests an important role of genetic factor. METHODS: Three hundred and ten healthy blood donors (controls), 98 CAD, 74 UBCa and 38 LCa patients were included in this pilot study. The influence of 92 single nucleotide polymorphisms (SNPs) and impact of cigarette smoking were analysed. RESULTS: Out of 92 SNPs tested, differences in distribution of 14 SNPs were detected between controls and patient groups. Only CTLA4 rs3087243 showed difference in both CAD and UBCa patient group compared to control group. Stratified by smoking status, the impact of smoking was associated to frequencies of 8, 3 and 4 SNPs in CAD, UBCa, LCa patients, respectively. None of these 92 SNPs showed a statistically significant difference to more than one type of disease among smoking patients. In non-smoking patients, 7, 3 and 6 SNPs were associated to CAD, UBCa, LCa, respectively. Out of these 92 SNPs, CTLA4 rs3087243 was associated to both non-smoking CAD and UBCa. The XRCC1 rs25487 was associated to both non-smoking UBCa and LCa. CONCLUSION: SNPs might be important risk factors for CAD, UBCa and LCa. Distribution of the SNPs was specific for each patient group, not a random event. Impact of cigarette smoking on the disease was associated to the specific SNP sequences. Thus, smoking individuals with SNPs associated to risk of these serious diseases is an important target group for smoking cessation programs.
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Fumar Cigarrillos/genética , Enfermedad de la Arteria Coronaria/genética , Predisposición Genética a la Enfermedad , Neoplasias Pulmonares/genética , Polimorfismo de Nucleótido Simple/genética , Neoplasias de la Vejiga Urinaria/genética , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Purpose: Individuals with immunoglobulin G deficiency (IgGsd) often complain of fatigue. The correlation between systemic inflammation and fatigue is unknown. In this study perceived quality of life (QoL) and fatigue in individuals with IgGsd, on and off immunoglobulin replacement therapy (IgRT) were correlated to inflammatory markers in plasma to identify the subgroup that benefits from IgRT. Method: Thirty-five IgGsd-patients were sampled on three occasions: at baseline, after being on IgRT for at least 18 months, and 18 months after discontinuation of IgRT. Short form 36, EQ-5D-5L visual analogue scale and fatigue impact scale questionnaires were used for evaluation of QoL and fatigue. Furthermore, a panel of 92 inflammatory markers were analysed in plasma. Thirty-two gender- and age-matched healthy individuals were included as controls and sampled on one occasion. Results: QoL was lower and perceived fatigue higher in IgGsd compared to the controls. Severe fatigue and low QoL were associated with the need to restart IgRT (which is considered in IgGsd-individuals with a high burden of infections in Sweden). Twenty-five inflammatory factors were dysregulated in IgGsd and the plasma protein patterns were similar regardless of whether IgRT was ongoing or not. Enrichment analysis indicated IL-10 signalling as the most affected pathway. Severe fatigue was associated with decreased levels of the neurotrophic factors VEGFA and CSF-1. Conclusion: Fatigue is a major contributory factor to impaired health-related QoL in IgGsd and is related to the need for IgRT. Low-grade systemic inflammation is a potential driver of fatigue. In addition to the burden of infections, we suggest the degree of fatigue should be considered when the decision to introduce IgRT is made.
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Fatiga/tratamiento farmacológico , Fatiga/inmunología , Deficiencia de IgG/inmunología , Inmunoglobulina G/uso terapéutico , Inflamación/inmunología , Encuestas y Cuestionarios , Adulto , Anciano , Quimiocina CXCL1/inmunología , Quimiocina CXCL1/metabolismo , Quimiocina CXCL5/inmunología , Quimiocina CXCL5/metabolismo , Fatiga/complicaciones , Femenino , Humanos , Deficiencia de IgG/complicaciones , Inmunoglobulina G/inmunología , Inflamación/complicaciones , Péptidos y Proteínas de Señalización Intercelular/inmunología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Interleucina-10/inmunología , Interleucina-10/metabolismo , Masculino , Persona de Mediana Edad , Calidad de Vida , Suecia , Adulto JovenRESUMEN
INTRODUCTION: A large body of evidence supports the association between psoriasis and concomitant diseases. However, the study of comedication for these diseases in patients with psoriasis is limited. The current study aimed to investigate the prescription and drug dispensation for comorbidity associated with psoriasis. METHODS: We conducted a retrospective case-control study from 9 April 2008 until 1 January 2016 using an electronic medical records database covering the entire population of the County of Jönköping and the Swedish Prescribed Drug Register. ICD-10 and Anatomical Therapeutic Chemical codes were used to identify patients with psoriasis and dispensed pharmaceutical prescriptions. Individuals without psoriasis were selected as controls. Patients receiving systemic treatment for psoriasis were considered as having moderate-severe psoriasis. Odds ratios for being dispensed pharmaceutical prescriptions and differences in mean number of dispensed prescriptions were explored. RESULTS: A total of 4587 patients with psoriasis were identified in the medical records, and 268,949 individuals served as controls. Patients with psoriasis had a significantly higher number of different drug dispensations compared to controls. Only 1.3% of all patients with psoriasis were without any prescription (excluding medication for psoriasis) during the study period while the number in the general population was 9.3%. Sex- and age-adjusted odds ratios for dispensation of drug groups related to comorbid disease were significantly higher among patients with psoriasis including drug groups such as anxiolytics and sedatives as well as drugs targeting COPD, migraine and erectile dysfunction. The most frequently dispensed comedications were oral antibiotics and analgesics including an increased risk for dispensation of opioids. Sex predisposed dispensation frequency for a variety of drug groups. Drugs targeting obesity, osteoporosis, psychiatric disease and anti-mycotics/-fungals were more frequent among women. CONCLUSION: Patients with psoriasis have significantly increased numbers of different dispensed prescriptions than those without psoriasis. This underlines previous findings on increased comorbidity and health care costs for patients with psoriasis.
RESUMEN
Studies have shown that mitochondrial DNA (mtDNA) can be exchanged between tissues; however, the mechanism(s) behind this phenomenon remain unclear. Exosomes and other extracellular vesicles (EVs) including microvesicles (MV) have been shown to contain mtDNA. EVs can be derived from a number of tissues; however, the source and relative proportion of EVs containing mtDNA remains unknown. We sampled whole blood and the EV fractions (exosome-enriched, MV-enriched, and apoptotic body-enriched) as well as several tissues (epithelial-cheek and urine sediment), connective (fibroblasts), and skeletal muscle in two subjects who received allogenic bone marrow transplants. Next generation sequencing of the mtDNA confirmed that all EV fractions contained mtDNA and most was derived from the donor, confirming that most of the EV fractions in the serum are bone marrow/blood cell-derived. Even after exposure to the donor mtDNA in EV fractions (and potentially free in the plasma) for years, there was little to no transfer of the donor mtDNA to the host mtDNA fraction in epithelial, connective, or skeletal muscle tissues. These data call into question the potential therapeutic use of bone marrow transplant or EV-based delivery systems for mtDNA-based disorders and establish bone marrow as the primary source of most of the mtDNA enriched EVs in serum.
Asunto(s)
Trastornos de Fallo de la Médula Ósea/terapia , Trasplante de Médula Ósea/métodos , Médula Ósea/metabolismo , ADN Mitocondrial/genética , Vesículas Extracelulares/patología , Mitocondrias/patología , Mutación , Adulto , Médula Ósea/patología , Vesículas Extracelulares/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Masculino , Mitocondrias/metabolismo , Donantes de Tejidos , Adulto JovenRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0210863.].